title: Apelin-36, a potent peptide, protects against ischemic brain injury by activating the PI3K/Akt pathway.
abstract: Apelin is an endogenous ligand of G protein-coupled receptor-apelin and angiotensin-1-like receptor (APJ). The biological effects of apelin-APJ system are reported in multiple systems including cardiovascular, endocrinal, and gastrointestinal system. Previous studies had shown that apelin-13 is a potential protective agent on cardiac ischemia; however, the role of apelin in the central nervous system remained unknown. In this study, we investigated therapeutic effects of apelin-36, a long form of apelin, in ischemic brain injury models. We found that apelin-36 reduced cerebral infarct volume in the middle cerebral artery occlusion (MCAO) model and the neonatal hypoxic/ischemic (H/I) injury model. Apelin-36 improved neurological deficits in the MCAO model and promoted long-term functional recovery after H/I brain injury. We further explored the protective mechanisms of apelin-36 on H/I brain injury. We clearly demonstrated that apelin-36 significantly reduced the levels of cleaved caspase-3 and Bax, two well-established apoptotic markers after H/I injury, indicating the anti-apoptotic activity of apelin-36 in ischemic injury. Since apelin-36 increased the level of phosphorylated Akt after H/I injury, we treated neonates with a specific PI3K inhibitor LY294002. We found that LY294002 decreased the phosphorylated Akt level and attenuated protective effects of apelin-36 on apoptosis. These suggested that the PI3K/Akt pathway was at least in part involved in the anti-apoptotic mechanisms of apelin-36. Our findings demonstrated that apelin-36 was a promising therapeutic agent on the treatment of ischemic brain injury.
authors.affiliation: Department of Neurology, The Affiliated Children Hospital of Soochow University, Suzhou, Jiangsu, China; Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Gu
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Lijing
authors.initials: L
authors.lastname: Zhai
authors.affiliation: Department of Neurology, The Affiliated Children Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: The Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Miao
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Ren
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Xuanchen
authors.initials: X
authors.lastname: Qian
authors.affiliation: Department of Neurology, The Affiliated Children Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Neurology, The Affiliated Children Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; The Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China. Electronic address: Xingshunxu@suda.edu.cn.
authors.forename: Xingshun
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China. Electronic address: liucf@suda.edu.cn.
authors.forename: Chun-Feng
authors.initials: CF
authors.lastname: Liu
mesh_terms: D054392:Adipokines; D000818:Animals; D000831:Animals, Newborn; D000073861:Apelin; D002545:Brain Ischemia / Q000517:prevention & control*; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D007276:Injections, Intraventricular; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009422:Nervous System Diseases / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051058:Oncogene Protein v-akt / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D054392:Adipokines; D000073861:Apelin; C402826:Apln protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt
keywords: 2,3,5-triphenyltetrazolium chloride; Apelin-36; Apoptosis; CCA; Cerebral ischemia; ECA; H/I; HIE; I/R; MCAO; PI3K/Akt; TTC; common carotid artery; external carotid artery; hypoxia/ischemia encephalopathy; hypoxic/ischemic; ischemia/reperfusion; middle cerebral artery occlusion